Reducing proteinuria slows the progression of chronic kidney disease. The current standard of care is to block of the renin - angiotensin system at various levels to reduce proteinuria. However, reduction of proteinuria is often incomplete, since other pathways involved in the pathogenesis or modification of proteinuria are not affected by this therapy. The long term goal of the PI's lab is to develop novel mechanism - based therapeutic agents that will reduce proteinuria and reduce the progression of chronic kidney disease due to glomerular disorders. Reducing the progression of chronic kidney disease to end stage kidney disease will have a major positive social and financial impact in the United States and worldwide. The PI's laboratory has discovered a major role of the circulating glycoprotein Angiopoietin-like-4 (Angptl4) in human and experimental nephrotic syndrome. Studies conducted by his team show that circulating Angptl4 is the first molecular link between proteinuria, hypoalbuminemia and hypertriglyceridemia, three major components of nephrotic syndrome. In glomerular disease, increased Angptl4 secretion from skeletal muscle, heart, liver and adipose tissue occurs when proteinuria becomes moderate to severe (in the human context, when it reaches nephrotic range). Circulating Angptl4 reduces proteinuria by binding to glomerular endothelial ?v5 integrin, while also inducing hypertriglyceridemia by inhibiting the activity of endothelium bound lipoprotein lipase. Further, it appears that this multi-organ upregulation of Angptl4 expression results from an increase in the plasma free fatty acid / albumin ratio. The PI has developed four new mutant forms of human Angptl4 protein that reduce proteinuria in rat models of focal and segmental glomerulosclerosis (FSGS) and diabetic nephropathy without significantly affecting plasma triglyceride levels. In Specific Aim 1, the relationship between elevated plasma free fatty acid / albumin ratio with increased peripheral organ Angptl4 expression in nephrotic syndrome will be investigated further using organ specific PPAR knockout mice. In Specific Aim 2, we will test whether administration of mutant human Angptl4 twice every month, or transgenic expression of rat Angptl4 from adipose tissue can reduce glomerulosclerosis and progression of chronic kidney disease in rats models of FSGS or diabetic nephropathy. In Specific Aim 3, mechanisms by which the interaction of circulating Angptl4 with glomerular endothelial ?v5 integrin reduces proteinuria will be investigated.